Prostaglandin E3 metabolism and cancer

Abstract

The anticancer activity of n-3 fatty acids, especially those derived from fish, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid) (DHA), has been studied for centuries. While there is a growing body of evidence that EPA and DHA may influence cancer initiation and development through targeting multiple events of tumor development, the underlying mechanisms responsible for these activities are still not fully understood. A number of studies have suggested that the anticancer activities of EPA and DHA are associated with their effects on eicosanoid metabolism by which they inhibit prostaglandin E2 (PGE2) production. In contrast to DHA, EPA can function as a substrate for cyclooxygenases (COXs) to synthesize unique 3-series prostaglandin compounds, especially PGE3. With advance technology in mass spectrometry, there is renewed interest in studying the role of PGE3 in EPA elicited anti-proliferative activity in various cancers, with some promising results. Here, we summarize the regulation of PGE3 synthesis in cancer cells and its role in EPA elicited anticancer activity. The development of PGE3 and its metabolites as potential biomarkers for future clinical evaluation of EPA and fish oil in cancer care is discussed.

Biomarkers for Personalizing Omega-3 Fatty Acid Dosing

“…While less relevant to the current model, EPA is metabolized by COX-2 to form PGE 3 , which has anti-prolfierative effects in cancer (38). The small amounts of PGE 3 found in the colon are likely due to EPA metabolism via COX-2.…”

ω-3 Polyunsaturated fatty acids-derived lipid metabolites on angiogenesis, inflammation and cancer

“…Compared with ARA, EPA is a poor substrate for COX enzymes 48, 49 . Previous studies have shown that PGE 3 has less detrimental or even beneficial effects on cancer, the biology of PGE 3 was discussed in a recent review 27 . PGE 3 has been shown to have less pro-inflammatory and pro-angiogenic effects than PGE 2 .…”

“…In a Matrigel-based Boyden chamber assay, PGE 3 inhibited cell invasion in the highly aggressive brain-metastatic melanoma 70W cell line 54 . The cellular receptors of PGE 3 have not been confirmed; some studies have shown that PGE 3 binds to the same receptors as PGE 2 with reduced affinity and potency 27, 55 . Further, a recent study showed that Δ 12 -prostaglandin J 3 (Δ 12 -PGJ 3 ), which is a novel COX-derived metabolite of EPA, potently inhibited progression of leukemia in animal models 56 .…”

“…Besides the heterogeneity of experimental designs, the mixed results could be, in part, due to inter-individual variations to metabolize ω-3 PUFAs to generate bioactive ω-3 lipid mediators (LMs) 23–26 . The ω-3 PUFAs act in part via formation of certain LMs such as cyclooxygenase (COX)-derived prostaglandin E 3 (PGE 3 ) 27 , lipoxygenase (LOX)-derived 4-hydroxy-docosahexaenoic acid (4-HDHA) 28 , cytochrome P450 (CYP)-derived epoxydocosapentaenoic acids (EDPs) 29 , as well as unique ω-3 lipid autacoids such as resolvins and protectins 30, 31 . These ω-3 LMs serve as autocrine and/or paracrine mediators to regulate inflammation and homeostasis 32 ; many of these mediators are short-lived, locally produced and locally acting in response to cellular stimuli, followed with degradation or metabolism to maintain homeostasis 33 .…”

Pharmacologic interventions for the prevention and treatment of retinopathy of prematurity

“…DHA and its precursor, eicosapentaenoic acid (EPA) reduce the formation of COX-2-derived PGE 2 (206), a metabolite of omega-6 PUFA-derived AA. COX-2-derived PGE 2 increases VEGF-stimulated invasiveness and angiogenesis through NF-κB (207). There is compelling evidence that EPA could function as a selective COX-2 inhibitor (207–209).…”